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Lázaro‐Gorines, Rodrigo; Pérez, Patricia; Heras‐Murillo, Ignacio; Adán‐Barrientos, Irene; Albericio, Guillermo; Astorgano, David; Flores, Sara; Luczkowiak, Joanna; Labiod, Nuria; Harwood, Seandean L.; Segura‐Tudela, Alejandro; Rubio‐Pérez, Laura; Nugraha, Yudhi; Shang, Xiaoran; Li, Yuxing; Alfonso, Carlos; Adipietro, Kaylin A.; Abeyawardhane, Dinendra L.; Navarro, Rocío; Compte, Marta; Yu, Wenbo; MacKerell, Alexander D.; Sanz, Laura; Weber, David J.; Blanco, Francisco J.; Esteban, Mariano; Pozharski, Edwin; Godoy‐Ruiz, Raquel; Muñoz, Inés G.; Delgado, Rafael; Sancho, David; García‐Arriaza, Juan; Álvarez‐Vallina, Luis
Advanced science, 12/2023, Letnik: 10, Številka: 34Journal Article
Administration of neutralizing antibodies (nAbs) has proved to be effective by providing immediate protection against SARS‐CoV‐2. However, dual strategies combining virus neutralization and immune response stimulation to enhance specific cytotoxic T cell responses, such as dendritic cell (DC) cross‐priming, represent a promising field but have not yet been explored. Here, a broadly nAb, TNT, are first generated by grafting an anti‐RBD biparatopic tandem nanobody onto a trimerbody scaffold. Cryo‐EM data show that the TNT structure allows simultaneous binding to all six RBD epitopes, demonstrating a high‐avidity neutralizing interaction. Then, by C‐terminal fusion of an anti‐DNGR‐1 scFv to TNT, the bispecific trimerbody TNTDNGR‐1 is generated to target neutralized virions to type 1 conventional DCs (cDC1s) and promote T cell cross‐priming. Therapeutic administration of TNTDNGR‐1, but not TNT, protects K18‐hACE2 mice from a lethal SARS‐CoV‐2 infection, boosting virus‐specific humoral responses and CD8+ T cell responses. These results further strengthen the central role of interactions with immune cells in the virus‐neutralizing antibody activity and demonstrate the therapeutic potential of the Fc‐free strategy that can be used advantageously to provide both immediate and long‐term protection against SARS‐CoV‐2 and other viral infections. Here they generate a bispecific Fc‐free trimeric antibody to neutralize and target SARS‐CoV‐2 virions to type 1 conventional dendritic cells and promote T cell cross‐priming. Therapeutic administration protected mice from a lethal infection, boosting virus‐specific humoral and CD8+ T cell immune responses. The results highlight the potential of bispecific trimerbodies with neutralizing and vaccine‐like action to provide both immediate and long‐term protection against SARS‐CoV‐2 and other viral infections.
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in: SICRIS
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